Abstract Among men who have sex with men (MSM), there is an urgent need to optimize the unprecedented clinical and public health benefits of pre-exposure prophylaxis (PrEP) to prevent HIV with those who use stimulants (i.e., methamphetamine, cocaine, and crack-cocaine). Stimulant-using MSM display 3-6 fold faster rates of HIV seroconversion, and one-in-ten MSM with newly diagnosed HIV infection report recent stimulant use. Findings from our team and others also demonstrate that stimulant use is a key obstacle to PrEP adherence and persistence. Stimulant-using MSM have a 3-fold greater rate of disengagement from PrEP care and 5-fold greater odds of sub-optimal PrEP adherence. The proposed multi-site randomized controlled trial (RCT) will leverage a promising intervention model of delivering a positive affect intervention during contingency management (CM), which we have recently demonstrated achieves durable and clinically meaningful reductions in viral load among HIV+, methamphetamine-using MSM. In the proposed multi-site RCT, we plan to test whether delivering an Affect Regulation Treatment to Enhance Medication Intervention Success (ARTEMIS) positive affect intervention during smartphone-based CM for directly observed PrEP doses achieves more durable reductions in HIV acquisition risk over 12 months. HIV acquisition risk (the primary outcome) will be operationalized as tenofovir diphosphate (TFV-DP) levels <700 fmol per punchand self- reported recent condomless anal sex (CAS). Up to 300 MSM on PrEP who report stimulant use and CAS in the past 3 months as well as any PrEP non-adherence in the past month will be recruited from social networking applications as well as PrEP clinical services in South Florida and San Francisco. Participants who meet the inclusion and exclusion criteria at an in-person baseline assessment will provide a dried blood spot (DBS) specimen that will be stored to measure TFV-DP levels and begin 3-months of smartphone-based CM that includes financial incentives for completing up to four directly observed PrEP doses per week (48 doses total over the 3 months). Participants will complete a run-in period (waiting period) where they will complete 4 directly observed smartphone-based CM PrEP doses prior to randomization. At a separate randomization visit, 240 participants (120 South Florida and 120 San Francisco) will be randomized to receive their first individually delivered ARTEMIS positive affect intervention or attention-control session. All 5 individually delivered intervention sessions will be delivered during the 3-month CM intervention period. Follow-up assessments will be conducted at 3, 6, and 12 months after beginning CM, with DBS collected to measure TFV-DP at 6 and 12 months. Consistent with the NIH OAR high priority area of ?reducing the incidence of HIV/AIDS,? this clinical research will meaningfully inform the targeted deployment of limited public health resources to optimize the unprecedented clinical and public health benefits of PrEP in stimulant-using MSM, one of highest priority populations for decreasing HIV incidence.